A CLINICALLY APPLICABLE, GENOMIC ASSAY DETECTS PATHOGENIC ALTERATIONS IN BARRETT’S ESOPHAGUS PATIENTS WITH NON-DYSPLASTIC TISSUE

Aims Current risk prediction for malignant progression in Barrett’s Esophagus (BE) is based on the histological diagnosis of dysplasia, which is limited by several factors. Genomic abnormalities precede dysplasia and may allow for objective and early risk stratification. We aimed to identify genomic factors to develop a clinically applicable targeted sequencing panel predicting progression in BE.

Methods Progressors (P) to high-grade dysplasia/esophageal adenocarcinoma (EAC) and matched non-progressors (NP) from a nested, community-based cohort were identified. DNA from baseline and subsequent (temporal) non-dysplastic endoscopies was assessed. Sequencing was performed utilizing a targeted capture-based panel designed to detect alterations previously identified in BE/EAC. Mutations, homozygous deletions, and high-level amplifications were filtered for likely pathogenic events.

Results 227 BE patients (85% male) with a median BE length of C3M4 were analyzed. 105 patients progressed after a median of 4 (IQR 3-6) years. 122 NP had a median follow-up of 6 (IQR 5-7) years. Mutations were more frequent in P compared with NP (73% vs. 55%, p=0.004, Table 1). Baseline analysis identified TP53 in 30% of P compared with 3% of NP, p=<0.0001, and increased to 50% closer to progression. TP53, KMT2D, ATM, and KDM6A were identified as risk predictors in univariate Cox regression analysis. Copy number alterations (amplifications, arm level loss) increased in P closer to progression.

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Conclusions We performed a genomic characterization of a large cohort of patients with NDBE, using a clinically applicable platform. Our study identified multiple mutational and copy number aberrations in non-dysplastic biopsies years before progression.

Publication History

Article published online:
14 April 2022